Study of a large Venezuelan kindred with Huntington's disease (HD) succeeded in localizing that gene to chromosome 4. Continued investigation of family members has narrowed the gap between the first linked marker and the defective allele itself. Advancing on the gene was made possible by the discovery of recombination events within members of the Venezuelan kindred and use of the Venezuelan Reference Pedigree, a selected subset of 62 sibships consisting of 872 potentially informative meioses, for high resolution genetic mapping. The size of the Venezuelan kindred, almost 10,000 individuals in the pedigree, and the volume of patients, 141 symptomatic and over 1000 at 50% risk for the disorder, make it ideal not only for isolating the HD gene but also for creating a reference map to identify other important genes as well. The aims of the grant are twofold: 1.) to investigate the Venezuelan HD kindred for the unique molecular and clinical tools it provides; and 2.) to extend the power which this pedigree brings to the molecular genetic search for the mutant HD allele to the search for other normal and aberrant genes throughout the human genome. The projects will be: 1.) To search the Venezuelan HD patient community for new recombination events, as they provide the keys to positioning the HD gene more accurately. 2.) To identify gene modifiers that may influence factors such as age of onset, juvenile expression, duration, or severity of expression, with the hope that these genes may be amenable to therapeutic manipulation. 3.) To search for genes which could influence an array of phenotypic variations, particularly psychiatric symptomatology, to assess clinical and genetic interactions in a large population with the same HD allele inherited from a progenitor and shared environment. 4.) To expand the brain donation program so that detailed neuropathology and neurochemistry can be done on tissues from these individuals who are exceptionally well characterized genetically and clinically. 5.) To verify that the complete dominance phenomenon described in probable HD homozygotes is true after examining a larger number for a longer time. 6.) To complete the collection of sufficient sibships to permit 1 centiMorgan or higher resolution mapping and 7.) to compare "consensus mapping", done with pooled data from disparate families, with "individual chromosome mapping", carried out by tracing the behavior of a specific chromosome though multiple generations and families.